Apo-Lamotrigine Special Precautions





Full Prescribing Info
Special Precautions
Skin Rash: There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of Apo-Lamotrigine treatment. The majority of rashes are mild and self-limiting, however, serious rashes requiring hospitalisation and discontinuation of Apo-Lamotrigine have also been reported. These have included potentially life-threatening rashes eg, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Reactions). It is not possible to predict reliably which rashes will prove to be life-threatening. Accordingly, Apo-Lamotrigine should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.
In adults enrolled in studies utilizing the current Apo-Lamotrigine dosing recommendations, the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately ½ of these cases have been reported as SJS (1 in 1000).
In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.
The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100.
In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first 8 weeks of therapy.
Additionally, the overall risk of rash appears to be strongly associated with: High initial doses of Apo-Lamotrigine and exceeding the recommended dose escalation of Apo-Lamotrigine therapy (see Dosage & Administration); concomitant use of valproate (see Dosage & Administration).
All patients (adults and children) who develop a rash should be promptly evaluated and Apo-Lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that Apo-Lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with Apo-Lamotrigine unless the potential benefit clearly outweighs the risk.
Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see Adverse Reactions). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multi-organ failure. It is important to note that early manifestations of hypersensitivity (eg, fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and Apo-Lamotrigine discontinued if an alternative aetiology cannot be established.
Hormonal Contraceptives: Effects of Hormonal Contraceptives on Apo-Lamotrigine Efficacy: An ethinyloestradiol/levonorgestrel (30 mcg/150 mcg) combination has been demonstrated to increase the clearance of lamotrigine by approximately 2-fold resulting in decreased lamotrigine levels (see Interactions).
Following titration, higher maintenance doses of lamotrigine (by as much as 2-fold) may be needed to attain a maximal therapeutic response. In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes 1 week of inactive medication (eg, "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive medication. These increases will be greater when lamotrigine dose increases are made in the days before or during the week of inactive medication. For dosing instructions, see General Dosing Recommendations for Apo-Lamotrigine in Special Patient Populations under Dosage & Administration.
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during Apo-Lamotrigine therapy and lamotrigine dosing adjustments may be needed.
Effects of Other Hormonal Contraceptive Preparations or HRT on Apo-Lamotrigine: Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of Apo-Lamotrigine on Hormonal Contraceptive Efficacy: An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see Interactions). The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with Apo-Lamotrigine cannot be excluded. A limited number of reports have been received of unexpected pregnancies and of menstrual bleeding disorders (eg, breakthrough bleeding) occurring with the concomitant use of Apo-Lamotrigine and hormonal contraceptives. Therefore, patients should be instructed to promptly report changes in their menstrual pattern ie, breakthrough bleeding while receiving Apo-Lamotrigine in combination with these medications.
Acute Multi-Organ Failure: Multi-organ failure, which in some cases has been fatal or irreversible, has been observed in patients receiving Apo-Lamotrigine. Fatalities associated with multi-organ failure and various degrees of hepatic failure have been reported in 2 of 3796 adult patients and 4 of 2435 paediatric patients who received Apo-Lamotrigine in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multi-organ failure have also been reported in compassionate plea and post-marketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus, overwhelming sepsis and hantavirus, making it difficult to identify the initial cause.
Additionally, 3 patients (a 45-year old woman, a 3.5-year old boy and an 11-year old girl) developed multi-organ dysfunction and disseminated intravascular coagulation 9-14 days after Apo-Lamotrigine was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both paediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with Apo-Lamotrigine was discontinued.
Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown.
Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Dihydrofolate Reductase: Lamotrigine is a weak inhibitor of dihydrofolate reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, Apo-Lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.
Renal Failure: In single-dose studies in subjects with end-stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.
Aseptic Meningitis: Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. Post-marketing cases of aseptic meningitis have been reported in paediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
Patients Taking Other Preparations Containing Lamotrigine: Apo-Lamotrigine should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
Epilepsy: As with other AEDs, abrupt withdrawal of Apo-Lamotrigine may provoke rebound seizures. Unless safety concerns (eg, rash) require an abrupt withdrawal, the dose of Apo-Lamotrigine should be gradually decreased over a period of 2 weeks.
There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multi-organ dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of Apo-Lamotrigine.
Bipolar Disorder: Clinical Worsening and Suicide Risk Associated with Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.
High risk patients eg, those with a history of suicidal behaviour or thoughts, young adults and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, appear to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset or were not part of the patient's presenting symptoms.
Effects on the Ability to Drive or Operate Machinery: Two volunteer studies have demonstrated that the effect of Apo-Lamotrigine on fine visual motor coordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with Apo-Lamotrigine, adverse events of a neurological character eg, dizziness and diplopia have been reported. Therefore, patients should see how Apo-Lamotrigine therapy affects them before driving or operating machinery.
Epilepsy: As there is individual variation in response to all antiepileptic drug therapy, patients should consult their physician on the specific issues of driving and epilepsy.
Haemophagocytic lymphohistiocytosis (HLH): HLH has occurred in patients taking lamotrigine. HLH is a syndrome of pathological immune activation, which can be life threatening, characterised by clinical signs and symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, high serum ferritin, hypertriglyceridaemia and abnormalities of liver function and coagulation. Symptoms occur generally within 4 weeks of treatment initiation.
Immediately evaluate patients who develop these signs and symptoms and consider a diagnose of HLH. Lamotrigine should be discontinued unless an alternative aetiology can be established.
Use in Pregnancy & Lactation: Administration of lamotrigine did not impair fertility in animal reproductive studies.
There is no experience of the effect of Apo-Lamotrigine on human fertility.
Post-marketing data from several prospective pregnancy registries have documented outcomes in over 2000 women exposed to Apo-Lamotrigine monotherapy during the 1st trimester of pregnancy. Whilst the data provide no evidence for a substantial increase in the overall risk of major birth malformations associated with Apo-Lamotrigine, one registry has reported an increase in the risk of isolated oral cleft malformations. This increased has not been confirmed in a pooled analysis of the data from six other registries.
The data on use of Apo-Lamotrigine in polytherapy combinations are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant Apo-Lamotrigine use.
As with other medicines, Apo-Lamotrigine should only be used during pregnancy if the expected benefits outweigh the potential risks.
Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during Apo-Lamotrigine therapy should be ensured.
There is limited information on the use of Apo-Lamotrigine in lactation. Preliminary data indicate that lamotrigine passes into breast milk in concentrations usually of the order of 40-60% of the serum concentration. In a small number of infants known to have been breastfed, the serum concentrations of lamotrigine reached levels at which pharmacological effects may occur.
The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant.
Use in Children: Children and Adolescents (<18 years): Bipolar Disorder: Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.
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